Droplet size prediction in the production of drug delivery microsystems by ultrasonic atomization.

Microencapsulation processes of drugs or other functional molecules are of great interest in pharmaceutical production fields. Ultrasonic assisted atomization is a new technique to produce microencapsulated systems by mechanical approach. It seems to offer several advantages (low level of mechanical stress in materials, reduced energy request, reduced apparatuses size) with respect to more conventional techniques. In this paper the groundwork of atomization is briefly introduced and correlations to predict droplet size starting from process parameters and material properties are presented.


I. INTRODUCTION
Microencapsulation is used to modify or to delay drug release. It offers greater effectiveness, lower toxicity and more lasting stability than conventional formulations. Spray-drying technique for preparation of microsystems presents several advantages compared to other microencapsulation techniques: it is, in principle, a continuous process, giving good reproducibility and potential for scale-up. Spray is usually generated by pressure and rotary nozzles, but they have some disadvantages, such as lack of control over the mean droplet size, broad droplet distributions, risk of clogging in case of suspensions. Moreover, they use only a small amount of their operating energy (centrifugal, pressure or kinetic energy) to shatter the liquid, while most of this energy is transformed into kinetic energy of the particles thus large settling chambers are required (summarizing: costs increase when speed of the atomized particles; increases) [1]. These disadvantages can be reduced using an ultrasonic atomizer: the ultrasound energy is transmitted with high efficiency to the liquid by a sonotrode, causing atomization. Despite ultrasonic nozzles have not been routinely used in laboratory scale spray-drying equipment, they can offer the generation of droplets, and consequently of microparticles, with a uniform size distribution [2].
In general, the atomization is defined as the disintegration of a liquid in drops in a surrounding gas by an atomizer [3]. The resultant suspension is defined as spray, mist, or aerosol. Atomization occurs owing to the competition between destructive and cohesive forces on the liquid surface, leading to fluctuations and disturbances in the liquid. The cohesive effect of liquid surface tension keeps the fluid in a status showing the lower surface energy, and the stabilizing effect of the viscosity tends to oppose any variation in liquid geometry. Instead, the external forces, such as aerodynamic, centrifugal, and electrostatic forces, act on the liquid surface promoting its disintegration. The initial process of disintegration or break-up is defined as primary atomization. However a number of larger droplets produced in the primary atomization can be unstable, thus reducing into smaller droplets. This process is usually defined as secondary atomization.
The effect of the forces acting on the liquid is resumed by the dimensionless numbers: (3) Where: Re = Reynolds number; We = Weber number; Oh = Ohnesorge number; ρ = liquid density; u = liquid velocity; d p = jet diameter (primary atomization) or drop diameter (secondary atomization); μ = liquid viscosity; σ = surface tension. The Reynolds number expresses the ratio between inertial and viscous forces. The Weber number is a measure of the relative importance of the fluid's inertia compared to its surface tension. By combining the two dimensionless numbers to eliminate the liquid velocity, the Ohnesorge number, containing fluid properties, is obtained. Thus, droplets diameter can be predicted by correlations mainly based on liquid properties (density, viscosity, surface tension), on atomizer geometry (orifice size) and on operative parameters, such as liquid flow rate. However, physical phenomena involved in the atomization processes have not been understood yet to such an extent to allow droplet size to be expressed by equations directly derived from the first principles. The correlations proposed are mainly based on empirical studies, even if the empirical correlations have been proved to be a practical way to determine droplet sizes from process parameters and relevant liquid/gas physical properties [3].

Droplet size prediction in the production of drug delivery microsystems by ultrasonic atomization
The empirical correlations are very useful in the forecast of microparticles size, especially if this feature plays a key role. In pharmaceutical applications microparticles size can affect rate and duration of release of entrapped therapeutic agents.

II. ULTRASONIC ATOMIZATION
When a liquid flows on a vibrating surface and splits into fine droplets, ultrasonic atomization occurs. A correlation proposed for the size diameter prediction of droplets produced by ultrasonic atomization, mainly based on the frequency f, was given by Lang [4]: (4) This correlation is only applicable when liquid phase viscosity and liquid flow rate have no effect on droplet size, but these parameters were proven to be very important in ultrasonic atomization. The dimensionless numbers, which dictate the droplets size, were modified in order to consider the dependence on physical-chemical properties and ultrasonic parameters. Therefore, the concept of critical Weber, for which inertial and surface tension forces are equilibrated (We c = 1) was extended to ultrasonic atomization, indicating the critical flow rate, Q c , as the threshold above which the flow rate influences the droplets size [5]. The critical flow rate was defined as: (5) Then, the maximum flow rate, above which dripping takes place forming larger droplets, is considered. The maximum flow rate is the volumetric displacement rate of vibrating surface, given by the product of frequency, f, amplitude of sound wave, Am, and area of vibrating surface, A. The amplitude, Am, is defined as: (6) where I is the power surface intensity (defined as the ratio between the power delivered at the surface, P, and the area of vibrating surface, A) and C is the speed of sound. The Weber number was thus modified to include the flow rate, Q, and the ultrasonic frequency, f: The Ohnesorge number was also modified taking into account that in ultrasonic atomization the growth of instability is given by the amplitude, Am: (8) Another dimensionless number, called Intensity number, I N , is defined to take into account the effect of energy density on droplets size: (9) From these dimensionless numbers, an universal correlation was proposed by Rajan and Pandit [5]: (10) The exponents in this correlation were chosen from experimental observations reported in literature.
Ramisetty et al. [6] also carried out experiments and developed a correlation applicable in the following ranges: f = 20-130 KHz; ρ = 912-1151 Kg m -3 ; σ = 0.0029-0.073 N m -1 ; Oh = 2.71 -161.64; We = 14.8 -571; I N = 3.65*10 -13 -1.92*10 -9 . The correlation was: (11) Avvaru et al. [7] made an attempt to include the rheological nature, pseudo-plasticity (non-Newtonian behaviour) of the atomizing liquid. In particular, they collected data to obtain a correlation for an aqueous solution of carboxy methyl cellulose (CMC), having a shear thinning behavior, with a flow behavior index n: (12) Barba et al. [8] proposed a modification of the correlation (10) by applying it to the ultrasonic atomization of alginate solutions: (13) Therefore, for the atomization of both Newtonian and non-Newtonian liquid, the following observations were done.
The droplet size decreases by increasing the frequency, f. At higher f, the liquid is subjected to a larger number of compression phases, thus the crest growth is reduced causing the eventual decrease of droplets size.
There is a range of liquid flow rate influencing the droplets size. Below a critical flow rate, Q c , the liquid cannot cover the whole atomizing surface, thus no effective atomization occurs. Above Q c , size is proportional to the liquid flow rate, again basing on film thickness on the atomization surface. Above a maximum flow rate, dripping occurs.
An increase in ultrasonic power causes an increase of the vibration amplitude (Am), leading to a broader distribution of droplets size. In effect, when power delivered to the tip is low, it can be freely used as soon as liquid spreads on the atomizer surface. Instead, at higher power, the liquid delivered on the surface immediately atomizes causing both a conical pattern of the spray and the exposition of the external part of the atomizer to air, being not wetted by the liquid.
The influence of viscosity becomes significant when it is greater than 10 cP [5]. The increase of liquid viscosity was shown to cause a reduction of droplets size. As the liquid viscosity increases, the liquid cannot be immediately atomized as it comes out from the hole. Therefore, the residence time of the liquid on the atomizing surface increases, causing liquid temperature rising, owing to the vibrational energy dissipation, and consequent decrease of liquid viscosity to a critical value.